The yeast Candida albicans is a normal resident of the human digestive tract. It is also the most common fungal pathogen of humans, causing both mucosal and systemic infections, particularly in immune compromised patients. This proposal seeks to understand how C. albicans orchestrates the formation of biofilms - resilient, surface-associated, organized groups of cells. Biofilm formation is medically relevant because new C. albicans infections are highly correlated with implanted medical devices, which provide efficient substrates for biofilm formation. The approach to studying biofilm formation outlined in this proposal is through dissection of the transcriptional network that controls this process. The ultimate goal is to understand how the individual target genes of the circuit contribute to the key properties of biofilms, such as drug resistance, cell-cell adhesion, cell-cell communication, and production of extracellular matrix. The candidate, Dr. Nobile, has a longstanding interest and history in research. Her career trajectory after the mentored phase of this K99 is to become an assistant professor at a leading academic research institute, where she hopes to continue and further her research program on biofilms, perform some teaching responsibilities, and train future scientists. Dr. Nobile believes that in the long-term, once more is known about how biofilms are regulated, her findings will provide important information to developing new drugs and vaccines to treat and prevent them. This K99/R00 proposal is designed to complement Dr. Nobile's prior research experience and to provide her with substantive and necessary technical and intellectual expertise as well as the confidence to function as an independent investigator. The training she will receive in the K99 phase will substantially enhance her career prospects, and make her highly competitive for faculty positions in top tier research institutes. Dr. Nobile's choices of primary mentor, Dr. Johnson, and co-mentor, Dr. Andes, were carefully selected for their relevant, diverse, and complementary expertise to cover all elements of her proposal. Both mentor and co-mentor are well-funded, internationally-recognized in their respective fields, and extremely productive. In addition, Dr. Nobile has assembled an advisory committee consisting of a diverse group of basic scientists and physicians to oversee her scientific progression and career development throughout her transition to becoming an independent investigator. All members of this committee are senior scientists/physicians with extensive experience in mentoring and advising postdocs as they transition to an independent academic career. PUBLIC HEALTH RELEVANCE: C. albicans is the most prevalent human fungal pathogen. It causes superficial infections in immunocompetent humans and life threatening, systemic infections in immunocompromised individuals. This proposal seeks to understand how C. albicans forms biofilms, communities of cells particularly resistant to mechanical force and antifungal drugs. C. albicans biofilms formed on implanted medical devices and are a major source of new infections. Understanding biofilms in more detail will lead to improvements in preventing and treating C. albicans infections.